This proposal represents a response to Program Announcement PAR-07-412 "Preapplication for Large- Scale Collaborative Project Award ". The applicants propose to create an interdisciplinary research consortium with the goal of integrating the rapidly evolving science of metabolomics with molecular pharmacology and pharmacogenomics to move toward the creation of a new discipline - "Pharmacometabolomics" a discipline that will transform our ability to individualize therapy. Specifically, we propose the formation of a multi-institution research consortium involving centers of excellence in metabolomics and metabolomic bioinformatics, joined with centers of excellence in molecular pharmacology and pharmacogenomic science. The purpose is to create an environment in which a cooperative iterative process of hypothesis generation, testing, and validation will be applied to achieve the union of metabolomic and pharmacologic science to create "Pharmacometabolomics". Achievement of that goal would have the potential to dramatically accelerate advances in our understanding of mechanisms of disease, drug action, and variation in response to therapy. It would provide a treating physician with knowledge and biomarkers that can reduce an inadequate trial-and-error process in selecting the right drug for each patient. Through a partnership with members of the Pharmacogenetics Research Network and leveraging large investments already made by NIH we plan to employ metabolomic analyses to study drug response phenotypes by using prototypic drugs used to treat cardiovascular and neuropsychiatric disease as "testbeds" for the development and application of Pharmacometabolomics. That process will generate broadly based, biochemically precise "metabolomic signatures" to complement and extend the clinical response phenotypes currently being used to select drugs and monitor drug therapy and also to complement and extend genomic, transcriptomic and proteomic information with regard to drug response. This process would result in the generation of new hypotheses that will be tested in experimental animal and cultured cell systems - leading, in turn, to new translational hypotheses to which metabolomic analyses could also be applied. The ultimate goal of the proposed research consortium would be the creation of an environment in which it will be possible to develop Pharmacometabolomics as a truly "interdisciplinary" biomedical discipline that can contribute to a "Systems Pharmacology" approach to the study of drug effects leading to a more personalized approach to therapy. PUBLIC HEALTH RELEVANCE: Pharmacometabolomics is the application of metabolomic science to understand drug effect and variation in drug response phenotypes. A "Therapeutic Revolution" has transformed modern drug therapy. Therefore, it is increasingly important that we understand which patients might best respond to drug therapy without suffering adverse drug reactions. Creation of the Pharmacometabolomics Research Network proposed in this application would have a significant public health impact by helping make it possible to better understand and individualize drug therapy.